Infection caused by drug-resistant bacteria has become one of the greatest threats to public health in the 21st century. Exploration for alternative therapeutic strategies is in a huge demand. One promising approach is to reinvestigate the known antibiotics and design their derivatives, in the hope of identifying novel antibiotic agents that combat antibiotic resistance. Hydantoins, the derivatives of 2,4-imidazolidinedione, have been developed for antibacterial applications for a long time. The mechanism of action for hydantoin derivatives is complex and not well understood, possibly due to a combination of various modes including damage to bacterial DNA, as well as binding to bacterial ribosomes to inhibit synthesis of critical bacterial enzymes, and so on. To date, one hydantoin derivative, nitrofurantoin, has been approved to treat urinary tract infections. As an old antibiotic, it has recently attracted considerable interest due to its low probability of bacterial resistance compared to other conventional antibiotics such as fluoroquinolones, possibly owing to the mixed mechanisms of action of hydantoins. However, hydantoin derivatives including nitrofurantoin generally exhibit only moderate antibacterial activity, which may limit their further application in combating emergent antibiotic resistance. For instance, nitrofurantoin shows a MIC (minimum inhibitory concentration) of 12.5 μg/mL for MRSA, and it is not even active towards P. aeruginosa up to 100 μg/mL.
Another alternative strategy to combat antibiotic resistance is to develop cationic host-defense peptides (HDPs) as potential antibiotic agents. Containing hydrophobic and cationic groups, HDPs and related peptidomimetics such as β-peptides, oligoureas, peptoids, AApeptides, and so forth, are able to selectively interact with negatively charged bacterial membranes, leading to membrane damage and subsequent bacterial cell death. Cationic charges are critical for association of these molecules with bacterial membranes, while hydrophobic groups are of importance for membrane penetration and disruption. HDPs and their derivatives are believed to minimize the probability of bacterial resistance development, as the membrane interaction and disruption is rather biophysical and lack specific membrane targets. It should be noted that besides membrane action, many HDPs could also permeate bacterial membranes and act on bacteria intracellular targets. Indeed, the mixed antibacterial mechanisms are expected to further synergize their ability to overcome bacterial resistance. Despite considerable enthusiasm, HDPs and oligomeric peptidomimetics encounter obstacles for practical applications, including moderate activity and systematic toxicity. In addition, their large molecular weights (normally >1000 Da) and structural complexity lead to tedious synthetic process and high production cost, hampering the therapeutic development of HDPs.